Acute lymphoblastic leukaemia (ALL) is an aggressive haematological tumour driven by the malignant transformation and expansion of B-cell (B-ALL) or T-cell (T-ALL) progenitors. The evolution of T-ALL pathogenesis encompasses different master developmental pathways, including the main role played by Notch in cell fate choices during tissue differentiation. Recently, a growing body of evidence has highlighted epigenetic changes, particularly the altered expression of microRNAs (miRNAs), as a critical molecular mechanism to sustain T-ALL. The immune response is emerging as key factor in the complex multistep process of cancer but the role of miRNAs in anti-leukaemia response remains elusive. In this review we analyse the available literature on miRNAs as tuners of the immune response in T-ALL, focusing on their role in Natural Killer, T, T-regulatory and Myeloid-derived suppressor cells. A better understanding of this molecular crosstalk may provide the basis for the development of potential immunotherapeutic strategies in the leukemia field.

BH3 mimetics, targeting the Bcl-2 family anti-apoptotic proteins, represent a promising therapeutic opportunity in cancers. ABT-199, the first specific Bcl-2 inhibitor, was approved by FDA for the treatment of several hematological malignancies. We have recently discovered IS21, a novel pan BH3 mimetic with preclinical antitumor activity in several tumor types. Here, we evaluated the efficacy of IS21 and other BH3 mimetics, both as single agents and combined with the currently used antineoplastic agents in T-cell acute lymphoblastic leukemia, ovarian cancer, and melanoma. IS21 was found to be active in T-cell acute lymphoblastic leukemia, melanoma, lung, pancreatic, and ovarian cancer cell lines. Bcl-xL and Mcl-1 protein levels predicted IS21 sensitivity in melanoma and ovarian cancer, respectively. Exploring IS21 mechanism of action, we found that IS21 activity depends on the presence of BAX and BAK proteins: complexes between Bcl-2 and Bcl-xL proteins and their main binding partners were reduced after IS21 treatment. In combination experiments, BH3 mimetics sensitized leukemia cells to chemotherapy, ovarian cancer cells and melanoma models to PARP and MAPK inhibitors, respectively. We showed that this enhancing effect was related to the potentiation of the apoptotic pathway, both in hematologic and solid tumors. In conclusion, our data suggest the use of inhibitors of anti-apoptotic proteins as a therapeutic strategy to enhance the efficacy of anticancer treatment.

BH3 mimetics, targeting Bcl-2 family anti-apoptotic proteins, represent a promising therapeutic opportunity in tumors. ABT-199, the first specific Bcl-2 inhibitor, has been approved by FDA for treating several hematological malignancies. We have recently discovered IS21, a novel pan BH3 mimetic with preclinical anti-tumor activity in different cancers. This study aimed to evaluate the efficacy of different BH3 mimetics both as single agents, in a panel of different tumor cell histotypes, and in combination with the currently used target therapy in ovarian cancer and melanoma. Our results demonstrate that IS21 reduced the viability of T-cell acute lymphoblastic leukemia, melanoma, lung, pancreatic and ovarian cancer cell lines, and that Bcl-xL and Mcl-1 protein levels were markers of IS21 sensitivity in melanoma and ovarian cancer, respectively. Exploring the IS21 mechanism of action, we reported that IS21 activity was dependent on BAX and BAK proteins, and complexes between Bcl-2 and Bcl-xL proteins and their main binding partners were reduced by IS21. In combination experiments, BH3 mimetics sensitized ovarian cancer cells to the treatment with PARP inhibitors, while IS21 and ABT-199 synergized with MAPK inhibitors in melanoma models both in vitro and in vivo. Through different methodological approaches, we evidenced that the potentiating effect of BH3 mimetics was related to enhancement of apoptotic pathway, both in melanoma and ovarian cancer. In conclusion, our data suggest the use of inhibitors of the anti-apoptotic proteins as a possible therapeutic strategy to enhance the efficacy of target therapy in ovarian cancer and melanoma.